2.7 Chemotherapy

Much progress has been made in using chemotherapy to inhibit HIV infections. The first target of anti-HIV drugs was the enzyme reverse transcriptase, an enzyme not present in human cells. These nucleoside reverse transcriptase inhibitors are analogs of nucleosides and cause the termination of the synthesis of viral DNA by competitive inhibition. There are other drugs that inhibit reverse transcription but

are not analogs of nucleic acids; these are the so-called non-nucleoside reverse transcriptase inhibitors.

To reproduce, the virus makes use of certain protease enzymes that cut proteins into pieces, which are then reassembled into the coat of new HIV particles. Drugs called protease inhibitors inhibit this enzyme and are now in use.

For infection to take place, the virus must accomplish a series of steps. It must attach to the cell's CD4 receptors, an interplay between the gp120 spike on the virus and the coreceptor must occur, and finally there must be a fusion with the cell to allow viral entry into the cell. One of the newer anti-HIV drugs, grouped as fusion inhibitors, targets the gp41 region of the viral envelope.

After fusion has been completed, reverse transcription produces a double-stranded cDNA version of HIV, which enters the nucleus. Within the nucleus, the complex containing the cDNA must be integrated into the host chromosome to form the HIV provirus. This step requires an enzyme, HIV integrase, which is a target for drugs called integrase inhibitors. Several other points of attack for anti-HIV drugs exist, and drugs such as maturation inhibitors, targeted at these are under investigation or are in clinical trials.

Because of the increasing number of drugs that control reproduction of the virus, at least temporarily, HIV infection is almost at the stage where it can be considered a treatable chronic disease-assuming that the treatment is affordable. The rapid reproductive rate and frequent occurrence of drugresistant mutations dictates that multiple drugs, given simultaneously, must be used. The current treatment is termed highly active antiretroviral therapy (HAART). This therapy consists of administering drug combinations; one of the most common combinations is two nucleoside analog reverse transcriptase inhibitors plus either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor. Patients are often required to take as many as 40 pills a day on a complex schedule, which must be adhered to rigorously because the virus is unforgiving. Even so, resistant strains of the virus are likely to emerge. As one scientist put it, drug resistance in HIV is driven by selective pressures that Darwin never imagined. Experience has also shown that eliminating all viruses in latent form in lymphoid tissue is especially difficult. The number of HIVs in circulation is often reduced to fewer than can be detected, but this is not the same as eradication. A caution is that a patient with a viral load at an undetectable level might still be infective. Frequent testing for viruses is required to follow effectiveness of the treatment. Arise in numbers probably indicates development of a resistant population.

One clearly successful application of chemotherapy has been to reduce the chance of HIV transmission from an infected mother to her newborn. The administration of even one nucleoside reverse transcriptase drug alone reduces the

incidence.

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